Dynamic borrowing from a single prior data source using the conditional power prior.

The conditional power prior is a popular method to borrow information from a single prior data source. The amount of borrowing is controlled by the power parameter which is fixed before running the new study. However, fixing this parameter before running a new study is often difficult and may be unwise because if the outcomes in the current study are much different from the prior data outcomes, the power parameter cannot be changed to reflect a more appropriate degree of borrowing. On the other hand, treating the power parameter as a random variable to be updated via Bayes theorem may relinquish control over how much to borrow in cases where regulatory oversight recommends a conservative approach.Previous authors have determined the power parameter at the end of the current study based on "stochastic" similarity in the outcomes between the current study and the prior data. In this paper, we introduce some modifications to those methods. First, we determine the power parameter based on similarity between a percentage of the current study outcome data available at an interim look and the prior outcome data. This may limit potential for operational bias resulting from the determination of the power parameter after the current study is complete. Next, we introduce a new measure of similarity between the current (interim) and prior data that limits similarity by a pre-specified clinical margin. The proposed clinical similarity region may be readily understood by clinicians who need to assess when such borrowing is clinically appropriate. Through simulations, we show that our approach has low bias and good power, while reducing type I error rate in areas outside of the "similarity region". An example of a hypothetical medical device study illustrates its potential use in practice.

Homogeneity assessment for pivotal medical device clinical studies.

A question that routinely arises in medical device clinical studies is the homogeneity across demographic subgroups, geographical regions, or investigational sites of the enrolled patients in terms of treatment effects or outcome variables. The main objective of this paper is to discuss statistical concepts and methods for the assessment of such homogeneity and to provide the practitioner a statistical framework and points to consider in conducting homogeneity assessment. Demographic subgroups, geographical regions, and investigational sites are discussed separately as each has its unique issues. Specific considerations are also given to randomized controlled trials, non-randomized comparative studies, and single-arm studies. We point out that judicious use of statistical methods, in conjunction with sound clinical judgment, is essential in handling the issue of homogeneity of treatment effect in medical device clinical studies.

Responder analysis without dichotomization.

In clinical trials, it is common practice to categorize subjects as responders and non-responders on the basis of one or more clinical measurements under pre-specified rules. Such a responder analysis is often criticized for the loss of information in dichotomizing one or more continuous or ordinal variables. It is worth noting that a responder analysis can be performed without dichotomization, because the proportion of responders for each treatment can be derived from a model for the original clinical variables (used to define a responder) and estimated by substituting maximum likelihood estimators of model parameters. This model-based approach can be considerably more efficient and more effective for dealing with missing data than the usual approach based on dichotomization. For parameter estimation, the model-based approach generally requires correct specification of the model for the original variables. However, under the sharp null hypothesis, the model-based approach remains unbiased for estimating the treatment difference even if the model is misspecified. We elaborate on these points and illustrate them with a series of simulation studies mimicking a study of Parkinson's disease, which involves longitudinal continuous data in the definition of a responder.

Adaptive Design Practice at the Center for Devices and Radiological Health (CDRH), January 2007 to May 2013.

Adaptive designs have generated great interest in the clinical trial community as a result of their versatility and efficiency. Recently, the Center for Devices and Radiological Health (CDRH) at the US Food and Drug Administration (FDA) surveyed all adaptive design applications submitted between 2007 and May 2013 for regulatory review. In this paper, we discuss the overall results and findings that emerged from an in-depth examination of the submissions. We summarize the current status of adaptive designs used in medical device studies. We also identify some of the lessons learned and common pitfalls that we encountered in our review of the designs.

Emergency department visits for medical device-associated adverse events among children.

OBJECTIVES: The purposes of this study were to provide national estimates of emergency department (ED) visits for medical device-associated adverse events (MDAEs) in the pediatric population and to characterize these events further. METHODS: ED medical record reports from the National Electronic Injury Surveillance System All Injury Program database from January 1, 2004, through December 21, 2005, were reviewed. MDAEs among pediatric patients were identified, and data were abstracted. National estimates for pediatric MDAEs were determined according to medical specialty, device category and class, injury diagnosis, and patient characteristics and outcome. RESULTS: The total estimated number of pediatric MDAEs during the 24-month period was 144,799 (95% confidence interval: 113,051-183,903), involving devices from 13 medical specialties. Contact lenses accounted for most MDAEs (23%), followed by hypodermic needles (8%). The distribution of MDAEs according to medical specialty varied according to age subgroup. The most-prevalent types of injuries included contusions/abrasions, foreign-body intrusions, punctures, lacerations, and infections. The most-frequently affected body parts were the eyeball, pubic region, finger, face, and ear. The majority of pediatric MDAEs involved class II (moderate-risk) devices. The incidence of pediatric MDAEs decreased with increasing age from early to late childhood and then spiked after 10 years of age. More girls than boys were affected at older ages (16-21 years) and more boys than girls at younger ages (< or =10 years). Hospitalizations were more likely to involve invasive or implanted devices. CONCLUSIONS: This study provides national estimates of pediatric MDAEs resulting in ED visits and highlights the need to develop interventions to prevent pediatric device-related injuries.

Natural antisense (rTSalpha) RNA induces site-specific cleavage of thymidylate synthase mRNA.

The 3' untranslated region (UTR) of rTSalpha RNA is complementary (i.e., antisense) to human thymidylate synthase (TS) RNA. When HEp2 cells (human epidermoid carcinoma) progressed from late-log to plateau phase growth, ribonuclease protection assay (RPA) revealed an inverse correlation between the levels of rTSalpha RNA and TS mRNA, suggesting a possible effect of rTSalpha RNA on TS mRNA levels. HEp2 cells expressing a Tet-On transactivator were transiently co-transfected with pHook-1 and a construct containing rTSalpha (protein and antisense RNA), rTSalphaDelta3' (rTSalpha protein only), rTSalpha-3' (antisense RNA-luciferase) or luciferase. Transfected cells were selected and evaluated for the effects of induced transgene expression on TS mRNA. Induced expression of transfected rTSalpha or rTSalpha-3', but not rTSalphaDelta3' or luciferase, resulted in decreased TS mRNA levels as measured by RPA. These results demonstrated that the antisense region of rTSalpha RNA is necessary and sufficient for this down-regulation of TS mRNA. RPA for TS mRNA also showed the enhanced appearance of two partial-length protected fragments in rTSalpha or rTSalpha-3' transfected cells. RPA stringency evaluations and primer extension assays indicated that TS mRNA is cleaved in vivo in a site-specific manner. These data demonstrate that rTS gene expression likely plays a role in down-regulating TS through a natural RNA-based antisense mechanism.